The present invention relates to amorphous solid borate-diol interaction products. More particularly, but not exclusively, the present invention relates to solid products formed by interaction of polymeric cis-1,2-diols with borate ion and suited for wound came and other uses.
The reaction of sodium tetraborate with cis-1,2-diols to form amorphous solids has been well documented, notably for polyvinyl alcohol, but also for naturally occurring materials such as konjac, guar and locust bean gum. Examples of the use of this reaction to prepare products suited for medical and related purposes are extensive.
EP-A 056,420 describes an eye gel of at least one ophthalmic medicament, polyvinyl alcohol (1 to 3%), a borate gelling agent (0.1 to 1.0%), and sterile water. The gel is maintained at a pH of 6.5 to 8.5, preferably 6.9 to 8.5. The ophthalmic gel is said to be a long acting, topical medicament which has a pH that is compatible with injured eyes and has uniform release characteristics.
U.S. Pat. No. 4,624,868 relates to dried absorbent particles, where guar gum as an exemplification of cis-1,2-diol polysaccharides is first hydrated then thickened by cross-linking with borax and finally dried to a powder to flake form, preferably by freeze drying. The resulting particles can absorb up to 100 times their weight or more of aqueous fluids such as urine and are employed in disposable diapers, bandages, and the like.
U.S. Pat. No. 4,362,781 describes a premoistened wiper comprising a non-woven web impregnated with a modified guar gum (phosphated, 5 to 14% of fiber weight) and wet with an aqueous lotion containing borate ions. The lotion also contains an organic hydroxy or keto acid or salt thereof (such as potassium citrate) capable of completing with borate ions.
U.S. Pat. No. 3,998,215 describes an electrically conductive pad conformable to the surface of the human body and adapted to facilitate the transfer of electrical signals between the body and an electrode. The pad comprises a porous, fibrous carrier having a lightly adherent, conductive hydrogel carried thereby, the hydrogel impregnating and surfacing both sides of the earner and the hydrogel being more cohesive to the hydrogel than adhesive to the surface of the human body to enable residue-free removal from the skin. The hydrogel can comprise a mixture of water, polyvinyl alcohol, sodium borate decahydrate and a fungicide, the water being present in at least about 70% by weight.
PCT/WO 95/17147 relates to fibers coated with particles of a galactomannan, or derivative thereof, cross-linked with borate. Guar and its derivatives are preferred.
U.K. Patent 1,174,139 is concerned with a dilutent composition which comprises a solution comprising;
(A) water,
(B) from 0.5 to 10%, by weight, based on the weight of the solution, of a water-soluble polymer of vinyl alcohol or an ester thereof,
(C) from 0.001 to 5% by weight, based on the weight of the solution, of an alkali metal borate or hydrate thereof, and
(D) from 5 to 10%. by weight, based on the weight of the solution, of a polyol.
Soviet Union Patent 1.795.672 describes a composition which contains (by weight) water 100, polyvinyl alcohol 4.7 to 14.07, sodium tetraborate 0.16 to 0.45, aerosil or white silica 3.75 to 11.25 and an acetamide or acrylamide or saccharose additive 0.23 to 7.5. The product has a gel-like or rubbery consistency and is prepacked in sectioned polyethylene capsules. Prior to use, the prepacked material is chilled in the freezing compartment of a domestic refrigerator. It can produce skin temperatures down to xe2x88x923 to xe2x88x927xc2x0 C. and can be recycled.
DE-A 4,007,668 is concerned with hydrogel foams based on gelatin and water optionally containing polyvinyl alcohol, together with a crosslinking agent which can be boric acid or a borate, and an organic or inorganic acid or salt, optionally with organic plasticizers and/or auxiliary agents and/or additives. The foam can be used for instance in the protection of wounds before drying out.
U.S. Pat. No. 5,071,648 relates to a composition comprising acetalized polyvinyl alcohol complexed with iodine, wherein the composition is capable of releasing free iodine in the presence of water. The acetalized polyvinyl alcohol may be further complexed with a borate. The acetalized PVA is preferably an hydroxylated polyvinyl acetal sponge.
PCT/WO 92/03172 is directed at a bandage, dressing or support matrix having a biocompatible open-pored plastic foam with a hydrogel embedded in the pores. The hydrogel is suitably formed from a borate-modified guar gum.
The present invention is directed at a different kind of interaction product which can be obtained from reaction of diols with borate. More especially, the present invention is concerned with amorphous solid products formed by interaction of polymeric cis-1,2-diols with borate ion and suited for wound care and other uses. Fluid handling and flow characteristics can be controlled and modified to fill specification needs.
PREFERRED EMBODIMENTS
At pH values between about 7.5 and 8.5, the borate ion from a borate salt or formed in situ from boric acid interacts with polymers containing cis-1,2-diols to form more viscous or amorphous solid systems. The polymeric diols can be synthetic, semi-synthetic, or natural. Some of the more common polymers undergoing this reaction are the polyvinyl alcohols and polysaccharides including galactomannans, such as guar and locust bean-gum, and glucomannans, such as konjac and Aloe (ace) mannans. Depending on the concentration of the polymer or polymers, the borate, and other additives, if any, the consistency can vary from somewhat viscous fluids to crisp amorphous solids. At selected concentrations of the components, the reaction products behave like self-restoring or healable solids that will flow at body temperatures. This property gives them possible value as wound-cavity fillers or wound putties. Other soluble and insoluble components can be added to impart desired properties, such as increased body-fluid absorption or fluid donation.
Although the principle use envisaged for the product of this invention is for the wound cavity-fillers, a number of other medical and non-medical markets can be envisioned. These possible uses include drug delivery, prosthetics and pads (fillers or in situ-formed coatings), and the toy and possibly executive stress-reliever markets.
For use as a wound cavity-filler, the product must be firm enough to handle, yet flow at body temperature to meet wound shape in about 10 to 30 seconds. The product needs to be easy to handle and either absorb or donate moisture, or both. Materials used must be biocompatible, non-toxic, and non-cytotoxic. In this respect, samples of PVA (5% and 20%) with added borate exhibited no cytotoxicity when tested on L929 mouse fibroblasts. Being sterilizable by gamma irradiation, autoclaving, or some other means is desirable.
Preparation of these amorphous solids preferably comprises forming a sol of the diol, and thermostable additives, if any, by dispersing the components in cool water, heating the mixture to boiling, adding hot aqueous sodium tetraborate, and allowing to cool. Other components can be added at suitable temperatures. If film preparation is desired, the hot sol can be distributed on a surface to form a film and the film is then used directly or is dried. For powders or granules, the solid diol can be triturated with a concentrated solution of sodium tetraborate or other borate source, with or without glycerol. For in situ-formed coatings, a sponge, cloth, gauze, or other material to be coated can be dipped into the hot mix, removed and drained, and optionally dried. Alternatively, the coatings can be applied by successively dipping the material to be coated into the borate solution, draining, blotting, blowing, or squeezing to remove the excess, if desired; dipping next into a cis-1,2-diol polymer solution, with or without additives; and finally again into the borate solution. If desired, this series can be repeated.
Spraying or some other means can be used as well as dipping, if appropriate. Again, the finished coated substrate can be maintained moist or partially or fully dried. In any form, the borate interaction products can be prepared and used alone, with internal and/or external supports, or as fillers in permeable or impermeable membranes.
Possible additives to the polymeric cis-1,2-diol reaction mixture used for any of the products are other borate-reactive and/or non-reactive hydrocolloids; reactive or non-reactive low molecular weight substances; insoluble particulates, both swellable and non-swellable, including charcoal and encapsulated chemical and/or biological reagents, ion-exchange resins, etc.; therapeutics; enzymes, antibodies; antimicrobials; etc.
When gelling hydrocolloids, such as agar, agarose, gellan, carrageenan, alginates or curdlan are added to the PVA or other diol before cross-linking, at concentrations where the hydrocolloid alone forms a firm gel, the combinations unexpectedly produce very elastic, almost putty-like compositions which can be stretched into films. The stretched film may have utility as a burn cover as well as a cavity filler. In this respect, the product from 5% PVA with 1.5 to 3.0% agar was particularly interesting.
With the addition of non-gelling hydrocolloids, such as hydroxyethylcellulose (HEC), carboxymethyl cellulose (CMC), and water soluble alginates to the PVA, absorptivity can be increased. The addition of certain borate-reactive polysaccharides, such as guar, can also increase absorptivity.
Polyvinyl alcohols of specific molecular weight ranges and degrees of hydrolysis, alone or as blends of different types, appear to be the best base polymeric cis-1,2-diols. The total concentration of the polyvinyl alcohol can range from 1% to 10% e.g. 5 to 10% (w/w) more or less. The borate is preferably sodium tetraborate used in an amount of 0.4% based on the total weight or 8% based on the weight of the polyvinyl alcohol, though other borate sources can be employed on the same molar basis. PVA types which have found to be most useful are the Polyviol G06/20, its near equivalent Polyviol G04/20 and Polyviol from Wacker Chemicals Ltd., Bridge Street, KT121AS, Walton-on-Thames, Surrey, U.K. The Sigma types P-1763 and P-8136 are similar to the Wacker PVAs. The borate is suitably added as a 2% aqueous solution of anhydrous sodium tetrabotate or as a 3.79% aqueous solution of sodium tetraborate decahydrate (borax), equivalent to the 2% of the anhydrous form.
Compositions of the invention for which the cis-1,2diol is polyvinyl alcohol may be produced so as to be such that when placed in a wound cavity they will flow sufficiently to fill all reaches of the cavity yet remain firm enough to be retained. Such a property is also referred to herein as a xe2x80x9cproper flow propertyxe2x80x9d at body temperature. Furthermore, such compositions may have optimum elasticity in that they may be formed into a coherent film, e.g. for use as a bum covering, face mask or similar application.
Details of preferred products in accordance with the invention which may be produced using polyvinyl alcohol as the cis-1,2-diol are given below.
One such preferred product is obtained using 0.1% to 1% by weight of borate and 1% to 10% by weight of a polyvinyl alcohol having a viscosity for 1% solution of 3 to 10 mPa s and a degree of hydroplysis of at least 75. Such a product more preferably comprises 3% to 7%, more preferably 4% to 6% and most preferably about 5% by weight of the polyvinyl alcohol. It is particularly preferred that the viscosity of the polyvinyl alcohol is 4 to 7 mPa s and most preferably about 6 mPa s. Preferably also the polyvinyl alcohol has a degree of hydrolysis of 75% to 85% most preferably about 80%. A particularly suitable example of polyvinyl alcohol for use in this embodiment of the invention is Polyviol G06/20 or its near equivalent G04/20.
Most preferably, the product as defined in the previous paragraph comprises 0.3% to 0.5%, and most preferably about 0.4%, by weight of borate.
A further preferred product is obtained from 0.1% to 1% by weight of borate and 1% to 10% by weight of a polyvinyl alcohol having a viscosity for a 1% solution of 25 to 30 mPa s and a degree of hydrolysis of at least 85%. Such a composition preferably comprises 3% to 7%, more preferably 4% to 6% and most preferably about 5% by weight of the polyvinyl alcohol. It is preferred that the viscosity of the polyvinyl alcohol (for a 1% solution) is 27 to 29 mPa s and most preferably about 28 mPa s. Moreover, it is preferred that the polyvinyl alcohol has a degree of hydrolysis of 85% to 95% and most preferably about 90%. A particularly suitable polyvinyl alcohol meeting these requirements is Polyviol G28/10.
The product as defined in the preceding paragraph preferably comprises 0.3% to 0.5% and most preferably about 0.4% by weight of borate.
A further preferred product in accordance with the invention may be obtained from 0.1% to 1% by weight of borate and a total of 1% to 10% by weight of a first polyvinyl alcohol of relatively low molecular weight and a second polyvinyl alcohol of relatively high molecular weight.
Preferably the ratio of the weight of the first polyvinyl alcohol to the second polyvinyl alcohol is greater than 1:1 and is more preferably 2:1 to 4:1, most preferably about 3:1.
This formulation may comprise a total of 4% to 6% by weight of the first and second polyvinyl alcohols, most preferably about 5% by weight.
The first polyvinyl alcohol is preferably one having a viscosity for a 1% solution of 3 to 10 mPa s, more preferably 4 to 7 mPa s. Preferably also the first polyvinyl alcohol has a degree of hydrolysis of at least 75%, more preferably 75% to 85% and most preferably about 80%. A particularly suitable first polyvinyl alcohol is Polyviol G06/20 or its near equivalent Polyviol G04/20.
The second polyvinyl alcohol is preferably one having a viscosity for a 1% solution of 25 to 30 mPa s, more preferably 27 to 29 mPa s and most preferably about 28 mPa s. Preferably also the second polyvinyl alcohol has a degree of hydrolysis of at least 85%, more preferably 85% to 95% and most preferably about 90%. A particularly suitable polyvinyl alcohol for use as the xe2x80x9csecond polyvinyl alcoholxe2x80x9d is Polyviol G28/10.
The product comprising the mixture of the first and second polyvinyl alcohols preferably comprises 0.3% to 0.5% by weight and more preferably about 0.4% by weight of borate.
A further preferred product is obtained from 0.1% to 1% by weight of borate and 1% to 10% by weight of a polyvinyl alcohol having a viscosity for a 1% solution of 8 to 16 mPa s and a degree of hydrolysis of at least 75%. Such a composition preferably comprises 3% to 7%, more preferably 4% to 6% and most preferably about 5% by weight of the polyvinyl alcohol. It is preferred that the viscosity of the polyvinyl alcohol (for a 1% solution) is 9 to 15 mPa s, more preferably 10 to 14 mPa s. Moreover, it is preferred that the polyvinyl alcohol has a degree of hydrolysis of 75% to 90% more preferably 80 to 85% and most preferably about 82 to 83%.
The product as defined in the preceding paragraph preferably comprises 0.3% to 0.5% and most preferably about 0.4% by weight of borate.
The products as defined in the last but one paragraph have properties similar to those obtained using a mixture of a first polyvinyl alcohol of relative low molecular weight and a second polyvinyl alcohol of relatively high molecular weight.
The above described products comprised of borate and polyvinyl alcohol may additionally comprise a hydrocolloid which may be a reactive hydrocolloid or a non-reactive hydrocolloid. The amount of hydrocolloid may be 1% to 5%, more preferably 2% to 4% by weight of the formulation.
The hydrocolloid may be a gelling hydrocolloid present in the formulation at a concentration at which the hydrocolloid alone forms a firm gel. The gelling hydrocolloid is preferably agar, agaros, gellan, carrageenan, curdalan or a gelling alginate in dissolved or particulate form. The hydrocolloid may be a non-gelling hydrocolloid, preferably hydroxyethyl cellulose or carboxymethyl cellulose.
The elastic wound putties of this invention can be dried into films, supported or unsupported, fully or partially dried, absorb synthetic body fluid and reassume the hydrated elastic composition. This same response occurs with powders of polyols to which borate solution, with or without glycerol, is added and triturated and the powder dried.
The use in controlled-release delivery systems is also envisaged, particularly for compositions having fluid donating properties.